Each year, in the U.S. alone, over 1.5 million people are diagnosed with cancer and approximately 600,000 people die of cancer. Numerous cancer therapeutics presently exist, however many of the known therapeutics are unable to treat and cure a significant number of cancer cases because they do not adequately target and destroy cancer cells.
Diagnosing cancer is an extremely important clinical practice. A large and growing number of cancer cases are diagnosed and monitored via positron emission tomography (PET) scans. PET scans consist of injecting a radiolabeled fluorinated glucose analog (FDG) into a patient and then detecting positrons emitted during radioactive decay of the FDG. Since FDG is structurally similar to glucose, it is internalized by the patient's cells in the same manner as glucose. The emitted positrons are detected and the emission pattern processed to produce an image. This image allows the location of the FDG in the patient to be determined.
PET is a powerful imaging method in the diagnosis of cancer because at least two-thirds (about 66%) of cancers exhibit an increased glucose metabolism in comparison to normal tissue. These cancers therefore internalize and metabolize FDG at a higher rate than other, non-cancerous tissues. As a result, the cancerous tissue shows a greater concentration of FDG than other, non-cancerous cells in a PET scan. The increased concentration of FDG in cancer tissue is seen as “hot spots,” or darker shaded images than normal tissue, on the PET scan.
PET scans can have a resolution of a few millimeters and may be quantitative. Therefore, small amounts of tissue can be resolved, and the quantitative rate of glucose metabolism in that small amount of tissue, can be determined.
In the 1950's Boron Neutron Capture Therapy (BNCT) was developed as a cancer therapeutic and tested in clinical trials. BNCT consists of injecting a boron-containing molecule into a patient that is then internalized by cancerous cells at a significantly greater rate than non-cancerous cells. The boron-containing molecule should therefore accumulate in cancerous cells. After a sufficient concentration difference of the boronated molecule has been achieved between the cancerous tissue and the neighboring non-cancerous tissue, the region of interest, which includes the cancerous tissue, is exposed to a beam of epithermal neutrons. Epithermal neutrons are low energy neutrons that penetrate and minimally interact with body tissue. However, epithermal neutrons strongly interact with boron. When an epithermal neutron collides with a boron atom, it yields a radioactive alpha particle—a highly biologically toxic form of ionizing radiation. Thus, when a boron molecule is located within a cell and an epithermal neutron collides with it, the released alpha particle may lead to cell damage, including death.
Clinical trials have been performed to investigate two potential boron-carrier molecules for BNCT: boronophenylalanine (boronated phenylalanine or BPA) and mercaptoundecahydrododecaborate (sodium borocaptate or BSH). Neither of these molecules, BPA nor BSH, is approved for routine clinical use. In part, this failure to be approved may have been due to the fact that neither molecule preferentially accumulates in cancer cells in sufficient amounts to distinguish the cancer tissue from normal tissue. Without sufficient accumulation, there will be little or no preferential targeting of cancer tissue by exposure to epithermal neutrons.
Another drawback of BNCT is that the absolute concentration of BPA or BSH in the cells of the patient cannot be measured or determined at the time of treatment (i.e., when the patient is exposed to a beam of epithermal neutrons). A healthcare provider, therefore, has no way of knowing whether a therapeutic level of boron has accumulated within the cancerous tissue. Likewise, the healthcare provider cannot be assured that a non-therapeutic level of boron exists in neighboring, non-cancerous tissue.
There is thus a need for improved targeting molecules that will enhance the effectiveness of BNCT. There is also a need for more accurate determination of the amount of the boron-carrying molecule located within the cancerous tissue and neighboring, non-cancerous tissue.